Pregnancy malaria is caused by a form of Plasmodium falciparum that sequesters in the placenta and evades preexisting immune responses. The proinflammatory response during placental malaria is related to severe maternal anemia and low birthweight, a major risk factor for infant mortality. Women become resistant over successive pregnancies as they acquire antibodies against placental parasites. This Project will examine the impact of four different Intermittent Preventive Treatment (IPTp) regimens for pregnancy malaria on immune responses related to protection and pathology, in order to illuminate disease pathogenesis and protective immunity during placental malaria. This proposed Project is based on the following hypotheses: efficacious IPTp regimens will reduce levels of maternal antibody that react with placental parasites, thereby increasing susceptibility to malaria in subsequent pregnancies; new IPTp regimens will reduce levels of maternal antibody that react with recombinant forms of placental parasite surface antigens, implicating; placental inflammatory infiltrates and inflammatory cytokine levels will be increased in women receiving sulfadoxine-pyrimethamine (SP) compared to women receiving more efficacious IPTp regimens. Based on our hypotheses, we expect the following outcomes: efficacious IPTp will delay the acquisition of specific immunity to placental parasites measured in binding-inhibition or flow cytometry assays, and may prevent boosting of existing responses in immune women. IPTp will delay or block the development of antibodies against malaria proteins identified recently as surface proteins of placental parasites, suggesting that these molecules play a role in placental malaria; IPTp will reduce placenta inflammation by limiting immune cell infiltration into the placenta and reducing proinflammatory cytokine responses, and these effects will be related to improved pregnancy outcomes. The proposed studies offer a unique opportunity to study the pathogenesis of placental malaria in the context of an IPTp trial that will stratify study participants into groups with clearly defined exposure to malaria. The broad objectives of this Project are to defme:the interaction between protective and pathologic immune responses in predicting pregnancy outcomes among malaria-exposed women, to define the benefits of efficacious IPTp, and to assess candidate antigens for a pregnancy malaria vaccine as targets of antibodies associated with protection.